Clinical events in a long‐term prospective neonatal cohort of children with sickle cell disease: Evidence for a high disease burden without systematic preventive intensification with hydroxyurea
Authors: Alizée Soulié, Annie Kamdem, Florent Neumann, Isabelle Hau, Fouad Madhi, Céline Delestrain, Mickaël Shum, Adèle Carlier‐Gonod, Aline Malterre, Harry Lezeau, Bassem Khazem, Ekaterina Belozertseva, Eric Guémas, Ralph Epaud, Serge Pissard, Cécile Arnaud, Corinne Pondarré
Journal: American Journal of Hematology (2023)

Newborn screening with comprehensive care has decreased early mortality and prevented overt stroke in many children with sickle cell disease (SCD).1, 2 Few studies have addressed the overall disease burden, and transfusion needs during childhood have yet to be assessed. Over the last three decades, the pediatric department of the Créteil Intercommunal University Hospital (CHIC), a referral center for SCD, has prospectively evaluated vaso-occlusive crisis (VOC), acute chest syndrome (ACS), hematological and major organ complications in a newborn cohort of children with SCD. According to national guidelines, hydroxyurea (HU) was administered to children after the recurrence of VOC or ACS, and transfusion program (TP) was implemented for stroke prevention. Specifically at our center, hematopoietic stem cell transplantation (HSCT) was also offered to patients with cerebral vasculopathy or frequent VOC/ACS with a human leukocyte antigen-identical sibling. We used the administration of disease-modifying therapies (DMT) including HU, TP, and HSCT, as a surrogate for disease severity. Our main objective was, therefore, to evaluate morbidity in children with SCD over a period beginning with the introduction of newborn screening (1986) and ending just before the introduction of preventive intensification with HU (2015). Kaplan–Meier (KM) survival estimates and the 95% confidence interval (95% CI) were calculated for all SCD-related complications, and use of DMT. Incidence rates were calculated as the number of events divided by total person-years (PY) at risk. PY after HSCT are excluded. This study was approved by our institutional ethics committee (no. 2021-07-02). This newborn inception cohort includes four SCD genotypes: SS and Sβ0 thalassemia (n = 289), sickle-hemoglobin C disease (SC n = 65), sickle β+ thalassemia (Sβ+ n = 32), and SDPunjab (SD n = 3), and it provides 4588 PY of observation. We considered individuals with the HbSS, HbSβ0, and HbSD genotypes as a single group (the severe sickle genotype group) because of the known clinical similarity of diseases and the small number of HbSD/Sβ0 subgroups. The median duration of follow-up (FU) was 13.2 (range: 1.2–23.6) years and 229 patients were still in FU at our center at the end of June 2021. Demographic and baseline biological characteristics, together with FU data are summarized in Table S1. Ten of the 389 patients died during FU, at a median age of 10.8 years (range: 1–20 years). Nine of these patients died from SCD-related causes, and all but one had HbSS disease. One death at 13 years was observed in a woman with HbSβ+ disease, due to massive pulmonary embolism right after a long air flight. The probability of survival at 5 years was 98.2% (95% CI: 96.6%–99.3%) for the total study population, with deaths observed only in the severe genotype group (97.6% [95% CI: 95.5%–99.0%]). Consistent with other SCD cohorts, at the age of 15 years, overall survival was 97.4% (95% CI: 95.4%–98.8%) for the total population, and 97.2% (95% CI: 95.0%–98.8%), 100% (95% CI: 100%–100%), and 90.9% (95% CI: 68.0%–100%) for the HbSS/SD/Sβ0, HbSC, and HbSβ+ genotype groups, respectively. Probabilities of acute SCD-related events (VOC, ACS, acute splenic sequestration [ASS], acute exacerbation of anemia [AEA], first transfusion, cholelithiasis, and DMT initiation) are shown in Figure 1A,B. The cumulative risk of major organ complications: elevated tricuspid regurgitation velocity (TRV) (above 2.5 m/s); sickle nephropathy (microalbuminuria defined by an albumin-to-creatinine ratio ≥30 mg/g); and sickle retinopathy (proliferative or not) are shown in Figure 1C. The long-term risks of cholecystectomy and splenectomy are shown in Figure S1. As reported in other neonatal cohorts, the earliest and most frequent events were VOC and ACS, the risks of both being significantly higher in HbSS/SD/Sβ° patients (with 50% of children experiencing at least one VOC by the age of 5 years and one ACS by the age of 10 years).1, 2 In our cohort, the 5-year probability of these events was slightly higher than the overall probability reported in the national retrospective study, undoubtedly reflecting the prospective nature of our study.1 The probabilities of these events did not differ significantly between the HbSC and HbSβ+ genotypes. Interestingly, the long FU for this cohort made it possible to detect less common events resulting from cumulative organ damage: by 15 years of age, the overall probability of a high TRV was 20.5% (95% CI: 15.6%–25.9%) for all genotypes and 23.7% (95% CI: 17.9–30.1) in the severe genotype group. As in many other studies, we defined a high TRV as a TRV of ≥2.5 m/s, as this threshold is associated with mortality in adults with SCD. TRV ≥2.7 m/s has more recently been shown to be a more appropriate definition of high TRV, and significantly associated with death in children, adolescents, and young adults.3 The risk of microalbuminuria was lower in our cohort than in other pediatric studies,4 reaching only 7.9 % (95% CI: 4.8%–11.6%) at 15 years, with no difference between the severe (8.7% [95% CI: 5.1%–13.2%]) and HbSC (6.6% [95% CI: 1.2–16.2]) genotypes. Whereas other published studies were cross-sectional, in this study, urine was sampled regularly from the age of 5 years, and at least two positive urine samples were required for diagnosis. Furthermore, we recently systematically tested urine samples collected in the recumbent position, to exclude orthostatic proteinuria. Alternatively, the widespread early use of DMT in the severe sickle genotype group may have decreased infarction and hemolysis-related glomerular damage, in turn influencing the development of sickle cell nephropathy. This study is the largest to date evaluating the incidence of retinopathy during childhood. Our findings confirm that retinopathy affects patients with the HbSC genotype at a much higher frequency, confirming the need for earlier screening in these children. Proliferative retinopathy developed as early as 7 years of age in one girl with HbSC disease, necessitating laser photocoagulation. DMT, reflecting severe disease, was introduced for 247 of the 292 children with HbSS/SD/Sβ° genotypes, at a median age of 4.1 years (0.5–17.8 years). By the age of 15 years, the probability of DMT initiation was 87.7% (95% CI: 83.3%–91.5%). Despite the widespread use of HU in the severe genotype group (probability of 64% [95% CI: 58.2%–69.8%] by the age of 10 years), substantial long-term morbidity due to acute complications of SCD was observed, with overall rates of 63.8/100 PY for VOC, 16.1/100 PY for ACS, 10.7/100 PY for AEA, and 6.9/100 PY for ASS (Figure 1D). These rates were unexpectedly similar to those reported in other neonatal cohorts taking into account only events occurring before the advent of DMT.2 First, our study did not address adherence to treatment, and HU dose was not recorded in our database. Moreover, HU was rarely increased to the maximal tolerated dose (MTD), as reflected by the moderate myelosuppression observed in another CHIC cohort (mean absolute neutrophil count 3.9 ± 1.9 x 109/L on HU at last check-up). This study provides new information about the overall transfusion requirements in SCD (Figure 1E): as expected, the transfusion burden is particularly heavy in the severe genotype group, with an incidence of transfusion episodes of 299/100 PY. Most transfusion episodes were delivered during chronic TP (245/100 PY). Primary stroke prevention accounted for most of the TP indications (33.5%). For children living in high-income settings, the 2020 American Society of Hematology guidelines suggest that HU treatment at the MTD can be considered to substitute for TP, in children with no severe vasculopathy, and after at least 1 year of regular blood transfusions. Certainly, this approach will decrease overall transfusion requirements. VOC and ACS recurrence despite HU accounted for 19.5% of the indications for TP initiation in our cohort. We believe that the recurrence of vaso-occlusive events driven by a sub-optimal HU dosing regimen could lead to patient discouragement, and explain in part over time nonadherence to HU. Considering trials demonstrating that dose escalation was safe and provided considerably greater clinical and biological benefits than 20 mg/kg per day dosing, we now consider HU earlier initiation with escalation to MTD in all young patients with HbSS/Sβ0 thalassemia.5 Finally, another frequent indication for the TP initiation in our study was prevention of ASS recurrence (17.8%). Interestingly, some of the strongest predictors of splenic function preservation in children treated with HU were a younger age at the initiation, a shorter time to reach MTD, and a greater increase of fetal hemoglobin from baseline.6 It is however unclear, whether early initiation of HU with rapid escalation to MTD might decrease the risk of ASS and the need for TP for ASS recurrence prevention. In conclusion, we report here the longest prospective neonatal cohort study to date addressing acute vaso-occlusive, hematological, and extracerebral major organ complications, and providing new data about transfusion requirements in SCD children. In the absence of preventive intensification with HU, SCD continues to cause substantial morbidity and the use of blood resources remains considerable. Several studies have reported beneficial effects of HU treatment, reducing recurrent episodes of pain, dactylitis, ACS, hospitalization, and transfusions. We believe that its preventive effects following early introduction and dosage escalation to the MTD should alter the course of the disease, and that its substitution for chronic transfusions to prevent primary stroke should decrease overall blood requirements. Involving individuals with SCD and their families in medical decision-making will be critical, to increase adherence to treatment. Recognition of the severity of the disease also provides a rationale for the early performance of genoidentical HSCT. Alizée Soulié and Corinne Pondarré cared for patients, designed the study, collected and interpreted the data, wrote the article, and took final responsibility for the decision to submit for publication. Ekaterina Belozertseva collected data. Eric Guémas carried out the statistical analysis. Florent Neumann collected and interpreted some data. Serge Pissard analyzed genetic markers. Bassem Khazem was involved in the collection of biological and transfusion data. Annie Kamdem, Cécile Arnaud followed patients, collected, and interpreted the data. Isabelle Hau, Fouad Madhi, Céline Delestrain, Mickaël Shum, Adèle Carlier-Gonod, Aline Malterre, Harry Lezeau, and Ralph Epaud cared for the patients. All the authors reviewed the paper and approved the final manuscript. We thank Dr. F. Bernaudin for the design of the database, for having collected data, and having provided care for study patients. We thank her for her important scientific contribution to the field of sickle cell disease. We thank all the patients and their families for participating in this study, and all the nurses from the various inpatient and outpatient units for their dedication. We thank Maxime Brussieux for collecting data. We thank Julie Sappa, from Alex Edelman & Associates, for English editing assistance. C.P. reports honoraria for Novartis and expert consultancy for Addmedica, Global Blood Therapeutics, and Pfizer. E.G. reports expert consultancy for Addmedica. All other authors declare no conflict of interest. All data generated or analyzed during this study are included in this published article. Figure S1. Kaplan–Meier curves indicating times to cholecystectomy and splenectomy. The green or solid line corresponds to children with severe sickle genotypes, the red or long dashed line to children with the HbSC sickle genotype, and the blue or short dashed line to children with the HbSβ+ sickle genotype. The numbers indicate the probability of event and the 95% confidence interval (in square brackets) at 15 years. Kaplan–Meier event-free survival estimates and 95% confidence intervals were compared between the three sickle genotype groups in log-rank tests. * indicates a significant difference (p < .05) between the severe and HbSC or HbSβ+ genotypes. ** indicate a significant difference (p < .001) between the severe and HbSC or HbSβ+ genotypes. Table S1. Follow-up data, demographic, and baseline biological characteristics for the neonatal sickle cell disease cohort. Baseline blood parameters were recorded outside of the context of transfusion or painful episodes and before the introduction of any disease-modifying therapy. The severe genotype group comprises the HbSS (n = 280), HbSβ0 thalassemia (n = 9), and HbSDpunjab (n = 3) sickle genotypes. G6PD, glucose-6-phosphate dehydrogenase. α-thalassemia refers to deletion of one or two α-chain genes. β Haplotypes: BAN, Bantou; BEN, Benin; SEN, Senegal; "Others" indicates all other combinations. The data shown are medians with (range) or mean ± SD. Groups were compared in Student's t-tests and Fisher's exact tests for quantitative and qualitative variables, respectively. * indicates a significant difference (p < .05) between the severe and HbSC or HbSβ+ genotypes. ** indicate a significant difference (p < .001) between the severe and HbSC or HbSβ+ genotypes. ¤ indicates a significant difference (p < .05) between the HbSC and HbSβ+ genotypes. Data S1. Methods including patient follow-up, definition of events, statistical analysis, and ethical considerations can be found online in the Supporting Information section at the end of this article. 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